In human populations, depression shows high-comorbidity with alcoholism. The Porsolt swim test (PST) is a commonly used behavioral screening test to identify compounds with antidepressant activity in humans. Further understanding of the neurobiological mechanisms involved in behavior in this test may be of value in understanding the pathophysiology of depression in humans, and thus may reduce the prevalence of some types of alcoholism. Towards this end, we have examined the behavior of different mouse strains on the PST, with the goal of identifying strains which differ in their behavior on this test for subsequent genetic analysis. We found that wild-derived mouse strains (CAST/Ei and SPRET/Ei) performed very differently on this test than commonly used laboratory strains (C57BL6, DBA/2, BalB C). We have carried out crosses between a wild derived (CAST/Ei) and laboratory (C57BL/6J) mouse strains, and tested the progeny on the PST. Based on analysis of the behavior of F1, backcross, and F2 mice, our data indicate that a major genomic locus is largely responsible for the difference in behavior between the two strains on the PST. We have now initiated a whole-genome linkage analysis to identify the genomic loci involved for the PST. This is being done on the ABI 377 sequencer using a panel of 150 STR loci evenly spaced throughout the genome at an average 20 cM resolution. Identification of genes which affect behavior in the PST is of potential relevance to understanding genetic factors in human depression, and may lead to the discovery of molecular targets for novel antidepressant drugs.